PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program leading to the career development of Dr. Sarah Huen as an independent physician-scientist. The principal investigator is a board-certified nephrologist who recently completed a Ph.D. program in Investigative Medicine at Yale University studying mechanisms of repair and fibrosis in ischemic kidney injury. Her career goal is to become an independent investigator studying sepsis- related acute kidney injury. She proposes to expand her training in immunobiology through an intensive training research experience under the mentorship of Dr. Ruslan Medzhitov, a pioneer in innate immunity and inflammation. In addition to didactic coursework and development of technical research skills in immunobiology and sepsis, an advisory committee comprised of scientists and physician-scientists with a broad range of expertise related to the project will provide both scientific and career development guidance. The research objective of this proposal is to determine the role of the expression of Fibroblast growth factor-21 (FGF21) by the kidney in the setting of sepsis. Preliminary data for this proposal reveal that in the mouse model of lipopolysaccharide (LPS) sepsis there is robust induction of FGF21 expression in the renal tubular epithelium. Mice deficient of FGF21 have more kidney dysfunction and are more susceptible to mortality in LPS sepsis. The induction of Fgf21 in the kidney is unique to sepsis as its expression is not induced in sterile hemodynamic injuries. The expression of renal Fgf21 in LPS sepsis can be inhibited by the reactive oxygen species (ROS) scavenger n-acetylcysteine. Our hypothesis is that FGF21 is a ROS-inducible kidney tissue protective pathway that is activated in response to sepsis. This hypothesis will be tested by pursuing these aims: 1) Determine the role of renal FGF21 in promoting survival in sepsis, and 2) Identify the stress response pathway and the source of ROS that regulate Fgf21 gene expression. The Yale University Departments of Nephrology and Immunobiology together have extensive scientific resources that will enable the successful achievement of these proposed aims. This proposal will define a novel renal defense mechanism activated in response to systemic infection while preparing the applicant to develop a successful independent research career as a physician-scientist.